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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Influence of dose and pharmaceutical formulation of vitamin A on plasma levels of retinyl esters and retinol and metabolic generation of retinoic acid compounds and beta-glucuronides in the cynomolgus monkey.

Retinoid concentrations were analyzed in plasma of nonpregnant female cynomolgus monkeys after oral administration of retinol or retinyl acetate at doses of 2, 10, or 50 mg (as retinol) per kilogram body weight dissolved in acetone/soybean oil (1/9) or acetone/Tween 20/water (1/5/4). All-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxoretinoic acid, and 13-cis-4-oxoretinoic acid as well as the conjugates of retinol and all-trans-retinoic acid with beta-D-glucuronic acid represented major polar plasma retinoids after high doses of vitamin A. The relative bioavailability of vitamin A as well as the biotransformation to more polar retinoids was independent of the molecular form of vitamin A (retinol or retinyl acetate) used for dosing. After administration of 2 mg/kg and, in particular, after a 10 mg/kg dose, the metabolic formation of polar retinoids in plasma was much more extensive with the detergent-based vehicle compared to the oil-based vehicle. At 50 mg/kg, comparable metabolism was observed for both forms. Polar metabolites of retinol were increased in a more than linear fashion with the detergent-based vitamin A preparations between 2 and 10 mg/kg and with the oil-based preparations between 10 and 50 mg/kg. Since retinoic acid compounds have previously been shown to be potent teratogens in various animal species and humans, their metabolic formation may be of significance for the teratogenic activity of high doses of vitamin A. In addition to the dose, the pharmaceutical preparation of vitamin A could therefore be a major determinant of the developmental toxicity of vitamin A.[1]


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